Despite the advent of effective statin therapies, atherosclerosis remains the leading cause of cardiovascular disease in the United States and worldwide. In addition to the well-known role of cholesterol as a major risk factor contributing to cardiovascular disease, evidence from many laboratories points to two other critical contributory factors, namely, dysregulated inflammation and metabolism. The latter two factors are inter- dependent, and metabolically active cells, in response to excess nutrient input, can generate a low-grade, chronic inflammation, referred to as metaflammation. This concept has become increasingly important as an epidemic of obesity in the Western world is driving the incidence of insulin resistance, diabetes, and athero- sclerosis, and consequent morbidity and mortality. The long-term goal of our Program Project is to gain a deep and mechanistic understanding of the genetic events and cellular and physiological processes underlying the connections between inflammation, metabolism, and atherogenesis. A central hypothesis is that macrophages are critically important early responders to metabolic stress, and that they in turn, by paracrine mechanisms, influence the responses of other cells crucial in metaflammation, particularly adipocytes and endothelial cells. The specific objectives of this Program are (i) to understand the molecular basis of interleukin-1 receptor/Toll- like receptor-mediated inflammatory responses in macrophages and EC, and delineate their roles in the initiation and pathogenesis of obesity-associated inflammatory disease (Project 1, Dr. Xiaoxia Li), (ii) to utilize mouse genetic, genomic, and proteomic approaches to identify atherosclerosis modifier genes and genetic modifiers of macrophage foam cell lipid droplet metabolism (Project 2, Dr. Jonathan Smith), and (iii) to determine the noncanonical function of glutamyl-prolyl tRNA synthetase (EPRS) as a critical effector of the mTORC1-S6K1 signaling pathway in adipocytes and macrophages, and its contribution to diet-induced obesity and atherosclerosis (Project 3, Dr. Paul Fox). The Project Leaders are a highly integrated and synergistic group employing distinct but complementary approaches, i.e., cell signaling (Li), mouse genetics/genomics/proteomics (Smith), and biochemistry (Fox). Three scientific Cores - Primary Cell and Mouse Metabolism, Atherosclerosis and Lipoprotein Analysis, and Macromolecular Interaction - and an Administration Core provide multi-project support, expertise, and service in a cost-effective manner, significantly strengthening each of the Projects. We anticipate our collaborative effort will lead to the discovery of novel genes, signaling pathways, and macro-molecular interactions that promote or restrict atherogenesis, and that can be leveraged to reduce disease initiation and progression, and support health and longevity.